Tag: Glioblastoma

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Strategies, considerations, and recent advancements in the development of liquid biopsy for glioblastoma

Neurosurg Focus 53 (6):E14, 2022

Glioblastoma (GBM) is a devasting primary brain tumor with less than a 5% 5-year survival. Treatment response assessment can be challenging because of inflammatory pseudoprogression that mimics true tumor progression clinically and on imaging. Developing additional noninvasive assays is critical. In this article, the authors review various biomarkers that could be used in developing liquid biopsies for GBM, along with strengths, limitations, and future applications. In addition, they present a potential liquid biopsy design based on the use of an extracellular vesicle–based liquid biopsy targeting nonneoplastic extracellular vesicles.

METHODS The authors conducted a current literature review of liquid biopsy in GBM by searching the PubMed, Scopus, and Google Scholar databases. Articles were assessed for type of biomarker, isolation methodology, analytical techniques, and clinical relevance.

RESULTS Recent work has shown that liquid biopsies of plasma, blood, and/or CSF hold promise as noninvasive clinical tools that can be used to diagnose recurrence, assess treatment response, and predict patient outcomes in GBM. Liquid biopsy in GBM has focused primarily on extracellular vesicles, cell-free tumor nucleic acids, and whole-cell isolates as focal biomarkers. GBM tumor signatures have been generated via analysis of tumor gene mutations, unique RNA expression, and metabolic and proteomic alterations. Liquid biopsies capture tumor heterogeneity, identifying alterations in GBM tumors that may be undetectable via surgical biopsy specimens. Finally, biomarker burden can be used to assess treatment response and recurrence in GBM.

CONCLUSIONS Liquid biopsy offers a promising avenue for monitoring treatment response and recurrence in GBM without invasive procedures. Although additional steps must be taken to bring liquid biopsy into the clinic, proof-of-principle studies and isolation methodologies are promising. Ultimately, CSF and/or plasma-based liquid biopsy is likely to be a powerful tool in the neurosurgeon’s arsenal in the near future for the treatment and management of GBM patients.

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Early Diagnosis and Surgical Intervention Within 3 Weeks From Symptom Onset Are Associated With Prolonged Survival of Patients With Glioblastoma

Neurosurgery 91:741–748, 2022

Glioblastoma (GBM) is a rapidly growing and most life-threatening malignant brain tumor. The significance of early treatment to the clinical outcomes of patients with GBM is unclear.

OBJECTIVE: To determine whether early diagnosis and surgery improve the preoperative and postoperative Karnofsky performance status (KPS) and prognosis of patients with GBM.

METHODS: Data of isocitrate dehydrogenase-wildtype patients with GBM treated at our institution between January 2010 and December 2019 were reviewed. Patients were classified into early or late diagnosis groups with a threshold of 14 days from initial symptoms. In addition, patients were divided into early, intermediate, and late surgery groups with thresholds of 21 and 35 days. Representative symptoms and patient prognoses were examined.

RESULTS: Of 153 patients, 72 and 81 were classified into the early and late diagnosis groups. The median tumor volume was significantly smaller in the former group. The proportion of patients with preoperative KPS scores ≥ 90 was 48.6%and 29.6% in the early and late diagnosis groups (P = .016). The early, intermediate, and late surgery groups included 43, 24, and 86 patients. The median overall survival was significantly longer in the early surgery group than in the late surgery group (28.4 vs 18.7 months, P = .006). Multivariate analysis demonstrated that significant predictors of shorter survival included extent of tumor resection (partial or biopsy), preoperative and postoperative KPS ≤ 60, and O6-methylguanine-DNA-methyltransferase promoter status (unmethylated).

CONCLUSION: Early diagnosis within 2 weeks and surgical interventions within 3 weeks from the symptom onset are associated with prolonged patient survival. Early GBM treatment will benefit patients with GBM.

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Laser Interstitial Thermal Therapy for First-Line Treatment of Surgically Accessible Recurrent Glioblastoma: Outcomes Compared With a Surgical Cohort

Neurosurgery 91:701–709, 2022

Laser interstitial thermal therapy (LITT) for glioblastoma (GBM) has been reserved for poor surgical candidates and deep “inoperable” lesions. We present the first reported series of LITT for surgically accessible recurrent GBM (rGBM) that would otherwise be treated with surgical resection.

OBJECTIVE: To evaluate the use of LITT for unifocal, lobar, first-time rGBM compared with a similar surgical cohort.

METHODS: A retrospective institutional database was used to identify patients with unifocal, lobar, first-time rGBM who underwent LITT or resection between 2013 and 2020. Clinical and volumetric lesional characteristics were compared between cohorts. Subgroup analysis of patients with lesions ≤20 cm 3 was also completed. Primary outcomes were overall survival and progression-free survival.

RESULTS: Of the 744 patients with rGBM treated from 2013 to 2020, a LITT cohort of 17 patients were compared with 23 similar surgical patients. There were no differences in baseline characteristics, although lesions were larger in the surgical cohort (7.54 vs 4.37 cm3 , P = .017). Despite differences in lesion size, both cohorts had similar extents of ablation/resection (90.7% vs 95.1%, P = .739). Overall survival (14.1 vs 13.8 months, P = .578) and progression-free survival (3.7 vs 3.3 months, P = 0. 495) were similar. LITT patients had significantly shorter hospital stays (2.2 vs 3.0 days, P = .004). Subgroup analysis of patients with lesions ≤20 cm 3 showed similar outcomes, with LITT allowing for significantly shorter hospital stays.

CONCLUSION: We found no difference in survival outcomes or morbidity between LITT and repeat surgery for surgically accessible rGBM while LITT resulted in shorter hospital stays and more efficient postoperative care.

 

 

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Outcome of glioblastoma resection in patients 80 years of age and older

Acta Neurochirurgica (2022) 164:373–383

Objective To evaluate the role and possible complications of tumor resection in the management of glioblastoma (GBM) in a series of patients 80 years of age and older with review of literature.

Methods The authors retrospectively analyzed cases involving patients 80 years or older who underwent biopsy or initial resection of GBM at their hospital between 2007 and 2018. A total of 117 patients (mean age 82 years) met the inclusion criteria; 57 had resection (group A) and 60 had biopsy (group B). Functional outcomes and survival at follow-up were analyzed.

Results Group A differed significantly from group B at baseline in having betterWHO performance status, better ASA scores, more right-sided tumors, and no basal ganglia or “butterfly” gliomas. Nevertheless, 56% of group A patients had an ASA score of 3. Median survival was 9.5 months (95% CI 8–17 months) in group A, 4 months (95% CI 3.5–6 months) in group B, and 17.5 months (95% CI 12–24 months) in the 56% of group A patients treated with resection and Stupp protocol. Rates of postoperative neurologic and medical complications were almost identical in the 2 groups, but the rate of surgical site complications was substantially greater in group A (12% vs 5%). There was no significant difference in mean preoperative and postoperative KPS scores (group A).

Conclusions In selected patients 80 years or older, radical removal of GBM was associated with acceptable survival and a low perioperative complication rate which is comparable to that of a biopsy. Although the median survival of the whole group was lower than reported for younger patients, a subgroup amenable to radical surgery and Stupp protocol achieved a median survival of 17.5 months.

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Influence of supramarginal resection on survival outcomes after gross-total resection of IDH–wild-type glioblastoma

J Neurosurg 136:1–8, 2022

The authors’ goal was to use a multicenter, observational cohort study to determine whether supramarginal resection (SMR) of FLAIR-hyperintense tumor beyond the contrast-enhanced (CE) area influences the overall survival (OS) of patients with isocitrate dehydrogenase–wild-type (IDH-wt) glioblastoma after gross-total resection (GTR).

METHODS The medical records of 888 patients aged ≥ 18 years who underwent resection of GBM between January 2011 and December 2017 were reviewed. Volumetric measurements of the CE tumor and surrounding FLAIR-hyperintense tumor were performed, clinical variables were obtained, and associations with OS were analyzed.

RESULTS In total, 101 patients with newly diagnosed IDH-wt GBM who underwent GTR of the CE tumor met the inclusion criteria. In multivariate analysis, age ≥ 65 years (HR 1.97; 95% CI 1.01–2.56; p < 0.001) and contact with the lateral ventricles (HR 1.59; 95% CI 1.13–1.78; p = 0.025) were associated with shorter OS, but preoperative Karnofsky Performance Status ≥ 70 (HR 0.47; 95% CI 0.27–0.89; p = 0.006), MGMT promotor methylation (HR 0.63; 95% CI 0.52–0.99; p = 0.044), and increased percentage of SMR (HR 0.99; 95% CI 0.98–0.99; p = 0.02) were associated with longer OS. Finally, 20% SMR was the minimum percentage associated with beneficial OS (HR 0.56; 95% CI 0.35–0.89; p = 0.01), but > 60% SMR had no significant influence (HR 0.74; 95% CI 0.45–1.21; p = 0.234).

CONCLUSIONS SMR is associated with improved OS in patients with IDH-wt GBM who undergo GTR of CE tumor. At least 20% SMR of the CE tumor was associated with beneficial OS, but greater than 60% SMR had no significant influence on OS.

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“Zooming in” on Glioblastoma: Understanding Tumor Heterogeneity and its Clinical Implications in the Era of Single-Cell Ribonucleic Acid Sequencing

Neurosurgery 88:477–486, 2021

Glioblastoma (GBM) is the most common primary brain malignancy in adults and one of the most aggressive of all human cancers. It is highly recurrent and treatment-resistant, in large part due to its infiltrative nature and inter- and intratumoral heterogeneity. This heterogeneity entails varying genomic landscapes and cell types within and between tumors and the tumor microenvironment (TME). In GBM, heterogeneity is a driver of treatment resistance, recurrence, and poor prognosis, representing a substantial impediment to personalized medicine.

Over the last decade, sequencing technologies have facilitated deeper understanding of GBM heterogeneity by “zooming in” progressively further on tumor genomics and transcriptomics. Initial efforts employed bulk ribonucleic acid (RNA) sequencing, which examines composite gene expression of whole tumor specimens. While groundbreaking at the time, this bulk RNAseq masks the crucial contributions of distinct tumor subpopulations to overall gene expression. This work progressed to the use of bulk RNA sequencing in anatomically and spatially distinct tumor subsections, which demonstrated previously underappreciated genomic complexity of GBM.

A revolutionary next step forward has been the advent of single-cell RNA sequencing (scRNAseq), which examines gene expression at the single-cell level. scRNAseq has enabled us to understand GBM heterogeneity in unprecedented detail.

We review seminal studies in our progression of understanding GBM heterogeneity, with a focus on scRNAseq and the insights that it has provided into understanding the GBM tumor mass, peritumoral space, and TME. We highlight preclinical and clinical implications of this work and consider its potential to impact neuro-oncology and to improve patient outcomes via personalized medicine.

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A Prospective Cohort Study of Neural Progenitor Cell-Sparing Radiation Therapy Plus Temozolomide for Newly Diagnosed PatientsWith Glioblastoma

Neurosurgery 87:E31–E40, 2020

In treating glioblastoma, irradiation of the neural progenitor cell (NPC) niches is controversial. Lower hippocampal doses may limit neurocognitive toxicity, but higher doses to the subventricular zones (SVZ) may improve survival.

OBJECTIVE: To prospectively evaluate the impact of limiting radiation dose to the NPC niches on tumor progression, survival, and cognition in patients with glioblastoma.

METHODS: Patients with glioblastoma received resection followed by standard chemoradiation. Radiation dose to the NPC niches, including the bilateral hippocampi and SVZ, was minimized without compromising tumor coverage. The primary outcome was tumor progression in the spared NPC niches. Follow-up magnetic resonance imaging was obtained bimonthly. Neurocognitive testing was performed before treatment and at 6- and 12-mo follow-up. Cox regression evaluated predictors of overall and progressionfree survival. Linear regression evaluated predictors of neurocognitive decline. RESULTS: A total of 30 patients enrolled prospectively. The median age was 58 yr. Median mean doses to the hippocampi and SVZ were 49.1 and 41.8 gray (Gy) ipsilaterally, and 16.5 and 19.9 Gy contralaterally. Median times to death and tumor progression were 16.0 and 7.6 mo, and were not significantly different compared to a matched historical control. No patients experienced tumor progression in the spared NPC-containing regions. Overall survival was associated with neurocognitive function (P ≤ .03) but not dose to the NPC niches. Higher doses to the hippocampi and SVZ predicted greater decline in verbal memory (P ≤ .01).

CONCLUSION: In treating glioblastoma, limiting dose to the NPC niches may reduce cognitive toxicity while maintaining clinical outcomes. Further studies are needed to confirm these results.

 

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Characterizing tumor invasiveness of glioblastoma using multiparametric magnetic resonance imaging

J Neurosurg 132:1465–1472, 2020

The objective of this study was to characterize the abnormalities revealed by diffusion tensor imaging (DTI) using MR spectroscopy (MRS) and perfusion imaging, and to evaluate the prognostic value of a proposed quantitative measure of tumor invasiveness by combining contrast-enhancing (CE) and DTI abnormalities in patients with glioblastoma.

METHODS Eighty-four patients with glioblastoma were recruited preoperatively. DTI was decomposed into isotropic (p) and anisotropic (q) components. The relative cerebral blood volume (rCBV) was calculated from the dynamic susceptibility contrast imaging. Values of N-acetylaspartate, myoinositol, choline (Cho), lactate (Lac), and glutamate + glutamine (Glx) were measured from multivoxel MRS and normalized as ratios to creatine (Cr). Tumor regions of interest (ROIs) were manually segmented from the CE T1-weighted (CE-ROI) and DTI-q (q-ROI) maps. Perfusion and metabolic characteristics of these ROIs were measured and compared. The relative invasiveness coefficient (RIC) was calculated as a ratio of the characteristic radii of CE-ROI and q-ROI. The prognostic significance of RIC was tested using Kaplan-Meier and multivariate Cox regression analyses.

RESULTS The Cho/Cr, Lac/Cr, and Glx/Cr in q-ROI were significantly higher than CE-ROI (p = 0.004, p = 0.005, and p = 0.007, respectively). CE-ROI had significantly higher rCBV values than q-ROI (p < 0.001). A higher RIC was associated with worse survival in a multivariate overall survival (OS) model (hazard ratio [HR] 1.40, 95% confidence interval [CI] 1.06–1.85, p = 0.016) and progression-free survival (PFS) model (HR 1.55, 95% CI 1.16–2.07, p = 0.003). An RIC cutoff value of 0.89 significantly predicted shorter OS (median 384 vs 605 days, p = 0.002) and PFS (median 244 vs 406 days, p = 0.001).

CONCLUSIONS DTI-q abnormalities displayed higher tumor load and hypoxic signatures compared with CE abnormalities, whereas CE regions potentially represented the tumor proliferation edge. Integrating the extents of invasion visualized by DTI-q and CE images into clinical practice may lead to improved treatment efficacy.

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Impact of Extent of Resection on Incidence of Postoperative Complications in PatientsWith Glioblastoma

Neurosurgery 86:625–630, 2020

Extent of resection (EOR) is well established as correlating with overall survival in patients with glioblastoma (GBM). The impact of EOR on reported quality metrics such as patient safety indicators (PSIs) and hospital-acquired conditions (HACs) is unknown.

OBJECTIVE: To perform a retrospective study to evaluate possible associations between EOR and the incidence of PSIs and HACs.

METHODS: We queried all patients diagnosed with GBM who underwent surgical resection at our institution between January 2011 and May 2017. Pre- and postoperative magnetic resonance imageswere analyzed for EOR. Each chart was reviewed to determine the incidence of PSIs and HACs.

RESULTS: A total of 284 patients met the inclusion criteria. EOR ranged from 39.00 to 100%, with a median of 99.84% and a mean of 95.7%. There were 16 PSI, and 13 HAC, events. There were no significant differences in the rates of PSIs or HACs when compared between patients stratified by gross total resection (EOR ≥ 95%) and subtotal resection (EOR < 95%). The odds of encountering a PSI or HAC were 2.5 times more likely in the subtotal resection group compared to the gross total resection group (P = .58). After adjusting for confounders, the odds of encountering a PSI or HAC in the subtotal resection group were 3.9 times greater than for the gross total resection group (P < .05).

CONCLUSION: Gross total resection of GBM is associated with a decreased incidence of PSIs and HACs, as compared to subtotal resection.

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An Online Calculator for the Prediction of Survival in Glioblastoma Patients Using Classical Statistics and Machine Learning

Neurosurgery, Volume 86, Issue 2, February 2020, Pages E184–E192

Although survival statistics in patients with glioblastoma multiforme (GBM) are well-defined at the group level, predicting individual patient survival remains challenging because of significant variation within strata.

OBJECTIVE: To compare statistical and machine learning algorithms in their ability to predict survival in GBM patients and deploy the best performing model as an online survival calculator.

METHODS: Patients undergoing an operation for a histopathologically confirmed GBM were extracted from the Surveillance Epidemiology and End Results (SEER) database (2005-2015) and split into a training and hold-out test set in an 80/20 ratio. Fifteen statistical and machine learning algorithms were trained based on 13 demographic, socioeconomic, clinical, and radiographic features to predict overall survival, 1-yr survival status, and compute personalized survival curves.

RESULTS: In total, 20 821 patients met our inclusion criteria. The accelerated failure time model demonstrated superior performance in terms of discrimination (concordance index = 0.70), calibration, interpretability, predictive applicability, and computational efficiency compared to Cox proportional hazards regression and other machine learning algorithms. This model was deployed through a free, publicly available software interface (https://cnoc-bwh.shinyapps.io/gbmsurvivalpredictor/).

CONCLUSION: The development and deployment of survival prediction tools require a multimodal assessment rather than a single metric comparison. This study provides a framework for the development of prediction tools in cancer patients, as well as an online survival calculator for patients with GBM. Future efforts should improve the interpretability, predictive applicability, and computational efficiency of existing machine learning algorithms, increase the granularity of population-based registries, and externally validate the proposed prediction tool.

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5-Aminolevulinic Acid Fluorescence-Guided Resection of 18F-FET-PET Positive Tumor Beyond Gadolinium Enhancing Tumor Improves Survival in Glioblastoma

Neurosurgery 85:E1020–E1029, 2019

The value of early postoperative 18F-FET-PET in patients with glioblastoma (GBM) is unclear. Five-aminolevulinic acid (5-ALA) is used for fluorescence-guided resections in these patients and previous data suggest that fluorescence and 18F-FET-PET both demarcate larger tumor volumes than gadolinium enhanced magnet resonance imaging (MRI).

OBJECTIVE: To correlate fluorescence with enhancing volumes on postoperative MRI and 18F-FET-PET tumor volumes, and determine the value of postoperative 18F-FET-PET for predicting survival through observational study.

METHODS: GBM patients underwent fluorescence-guided resection after administration of 5-ALA followed by early postoperative MRI and 18F-FET-PET for determination of residual tissue volumes. All patients were treated with standard temozolomide radiochemotherapy and monitored for progression-free and overall survival (PFS, OS).

RESULTS: A total of 31 patients were included. For functional reasons, residual 5-ALA derived fluorescent tissue was left unresected in 18 patients with a median 18F-FETPET volume of 17.82 cm3 (interquartile range 6.50-29.19). In patients without residual fluorescence, median 18F-FET-PET volume was 1.20 cm3 (interquartile range 0.87-5.50) and complete resection of gadolinium enhancing tumor was observed in 100% of patients. A 18F-FET-PET volume of above 4.3 cm3 was associated with worse OS (logrank P-value≤.05), also in patients with no residual contrast enhancing tumor on MRI. More patients in whom fluorescencing tissue had been removed completely had postoperative 18F-FET-PET tumor volumes below 4.3 cm3.

CONCLUSION: Postoperative 18F-FET-PET volumes predict OS and PFS. Resection of 5-ALA derived fluorescence beyond gadolinium enhancing tumor tissue leads to lower postoperative 18F-FET-PET tumor volumes and improved OS and PFS without additional deficits.

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Comparative Analysis of Subventricular Zone Glioblastoma Contact and Ventricular Entry During Resection in Predicting Dissemination, Hydrocephalus, and Survival

Neurosurgery, Volume 85, Issue 5, November 2019, Pages E924–E932

Ventricular entry during glioblastoma resection and tumor contact with the subventricular zone (SVZ) have both been shown to associate with development of hydrocephalus, leptomeningeal dissemination, distant parenchymal recurrence, and decreased survival. However, prior studies did not analyze these variables together in a single-patient population; therefore, it is unknown which is an independent predictor of these outcomes.

OBJECTIVE: To conduct a comparative outcome analysis of surgical ventricular entry and SVZ contact by glioblastoma in a retrospective cohort of 232 patients.

METHODS: Outcomes studied included hydrocephalus, leptomeningeal dissemination, distant tumor recurrences, and progression-free (PFS) and overall (OS) survival. The Cox proportional regression analyses were adjusted for age at diagnosis, preoperative Karnofsky performance status score, extent of resection, temozolomide and radiation treatments, and tumor molecular status (specifically, IDH1/2 mutation and MGMT promoter methylation).

RESULTS: Surgical ventricular entry, SVZ-contacting glioblastoma, hydrocephalus, leptomeningeal dissemination, and distant recurrences were observed in 85 (36.6%), 114 (49.1%), 19 (8.2%), 78 (33.6%), and 59 (25.4%) patients, respectively. Multivariate, adjusted analysis revealed SVZ tumor contact—but not ventricular entry—associated with hydrocephalus (hazard ratio, HR, 4.20 [1.13-15.7], P = .03), leptomeningeal dissemination (HR 1.93 [1.14-3.28], P = .01), PFS (HR 2.10 [1.53-2.88], P < .001), and OS (HR 1.90 [1.35-2.67], P < .001). Distant recurrences were not associated with either. No interaction between the 2 variables was statistically noted.

CONCLUSION: SVZ contact by glioblastoma was independently associated with the development of hydrocephalus, leptomeningeal dissemination, and decreased survival. SVZ tumor contact was associated with ventricular entry during surgical resections, which did not independently correlate with these outcomes.

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Insular glioma surgery: an evolution of thought and practice


J Neurosurg 130:9–16, 2019

The goal of this article is to review the history of surgery for low- and high-grade gliomas located within the insula with particular focus on microsurgical technique, anatomical considerations, survival, and postoperative morbidity.

METHODS The authors reviewed the literature for published reports focused on insular region anatomy, neurophysiol- ogy, surgical approaches, and outcomes for adults with World Health Organization grade II–IV gliomas.

RESULTS While originally considered to pose too great a risk, insular glioma surgery can be performed safely due to the collective efforts of many individuals. Similar to resection of gliomas located within other cortical regions, maximal resection of gliomas within the insula offers patients greater survival time and superior seizure control for both newly diagnosed and recurrent tumors in this region. The identification and the preservation of M2 perforating and lateral len- ticulostriate arteries are critical steps to preventing internal capsule stroke and hemiparesis. The transcortical approach and intraoperative mapping are useful tools to maximize safety.

CONCLUSIONS The insula’s proximity to middle cerebral and lenticulostriate arteries, primary motor areas, and perisyl- vian language areas makes accessing and resecting gliomas in this region challenging. Maximal safe resection of insular gliomas not only is possible but also is associated with excellent outcomes and should be considered for all patients with low- and high-grade gliomas in this area.

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The relationship between repeat resection and overall survival in patients with glioblastoma: a time-dependent analysis

J Neurosurg 129:1231–1239, 2018

Previous studies assessed the relationship between repeat resection and overall survival (OS) in patients with glioblastoma, but ignoring the timing of repeat resection may have led to biased conclusions. Statistical methods that take time into account are well established and applied consistently in other medical fields. The goal of this study was to illustrate the change in the effect of repeat resection on OS in patients with glioblastoma once timing of resection is incorporated.

METHODS The authors conducted a retrospective study of patients initially diagnosed with glioblastoma between January 2005 and December 2014 who were treated at Memorial Sloan Kettering Cancer Center. Patients underwent at least 1 craniotomy with both pre- and postoperative MRI data available. The effect of repeat resection on OS was assessed with time-dependent extended Cox regression controlling for extent of resection, initial Karnofsky Performance Scale score, sex, age, multifocal status, eloquent status, and postoperative treatment.

RESULTS Eighty-nine (55%) of 163 patients underwent repeat resection with a median time between resections of 7.7 months (range 0.5–50.8 months). Median OS was 18.8 months (95% confidence interval [CI] 16.3–20.5 months) from initial resection. When timing of repeat resection was ignored, repeat resection was associated with a lower risk of death (hazard ratio [HR] 0.62, 95% CI 0.43–0.90, p = 0.01); however, when timing was taken into account, repeat resection was associated with a higher risk of death (HR 2.19, 95% CI 1.47–3.28, p < 0.001).

CONCLUSIONS In this study, accounting for timing of repeat resection reversed its protective effect on OS, suggesting repeat resection may not benefit OS in all patients. These findings establish a foundation for future work by accounting for timing of repeat resection using time-dependent methods in the evaluation of repeat resection on OS. Additional recommendations include improved data capture that includes mutational data, development of algorithms for determining eligibility for repeat resection, more rigorous statistical analyses, and the assessment of additional benefits of repeat resection, such as reduction of symptom burden and enhanced quality of life.

 

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Is surgical resection useful in elderly newly diagnosed glioblastoma patients?

Acta Neurochirurgica (2018) 160:1779–1787

The incidence of glioblastoma among elderly patients is constantly increasing. The value of radiation therapy and concurrent/adjuvant chemotherapy has been widely assessed. So far, the role of surgery has not been thoroughly investigated. The study aimed to evaluate safety and impact of several entities of surgical resection on outcome of elderly patients with newly diagnosed glioblastoma treated by a multimodal approach.

Methods Patients ≥ 65 years, underwent surgery were included. The extent of surgical resection (EOR) was defined as complete resection (CR = 100%), gross total resection (GTR = 90–99%), sub-total resection (STR = 78–90%), partial resection (PR = 30– 78%), and biopsy. After surgery, all patients received adjuvant radiotherapy (60/2 Gy fraction) with concomitant/adjuvant temozolomide chemotherapy.

Results From March 2004 to December 2015, 178 elderly with a median age of 71 years (range 65–83 years) were treated. CR was obtained in 8 (4.5%), GTR in 63 (35.4%), STR in 46 (25.8%), PR in 16 (9.0%), and biopsy in 45 (25.3%). RTwas started in all patients, concurrent/adjuvant CHTin 149 (83.7%) and 132 (74.2%). The median follow-up time was 12.2 months (range 0.4– 50.4 months). The median, 1- and 2-year progression-free survival was 8.9 months (95%CI 7.8–100 months), 32.0 ± 3.5%, and 12.9 ± 2.6%. The median, 1- and 2-year overall survival were 12.2 (95%CI 11.3–13.1 months), 51.1 ± 3.7%, and 16.3 ± 2.9%. Tumor location, extent of resection, and neurological status after surgery statistically affected survival (p ≪ 0.01).

Conclusion Maximal surgical resection is safe and feasible in elderly patients with influence on survival. A preoperative evaluation has to be carried out.

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Thalamic Glioblastoma: Clinical Presentation, Management Strategies, and Outcomes

Neurosurgery 83:76–85, 2018

Thalamic glioblastomas (GBMs) represent a significant neurosurgical challenge. In view of the low incidence of these tumors, outcome data and management strategies are not well defined.

OBJECTIVE: To identify the natural history and factors associated with survival in patients with thalamic glioblastoma.

METHODS: A retrospective review of all patients with thalamic glioblastoma over a 10-yr period was performed. Presenting clinical, radiological, and outcome data were collected. Chi-squared and Fisher’s exact tests were used to compare clinical characteristics across tumor groups. Cox proportional hazard models were utilized to investigate variables of interest with regard to overall survival.

RESULTS: Fifty-seven patients met inclusion criteria, with a median age of 53 and median Karnofsky Performance Scale (KPS) score of 80. The most common presenting symptoms were weakness, confusion, and headache. Hydrocephalus was present in 47% of patients preoperatively. Stereotactic biopsy was performed in 47 cases, and 10 patients underwent craniotomy. The median overall survival was 12.2 mo. Higher KPS, younger age, and cerebrospinal fluid (CSF) diversionwere correlatedwith better overall survival univariately, respectively, while the presence of language deficits at initial presentation was associated with poorer survival. In multivariate analysis, the only significant predictor of survival was presenting KPS.

CONCLUSION: The overall survival of patients with thalamic glioblastoma is comparable to unresectable lobar supratentorial GBMs. Younger patients and those with good presenting functional status had improved survival. Midbrain involvement by the tumor is not a negative prognostic factor. Improved therapies are needed, and patients should be considered for early trial involvement and aggressive upfront therapy.

 

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Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma

J Clin Oncol 36. © 2018

https://doi.org/10.1200/JCO.2017.75.8219

DNX-2401 (Delta-24-RGD; tasadenoturev) is a tumor-selective, replication-competent oncolytic adenovirus. Preclinical studies demonstrated antiglioma efficacy, but the effects and mechanisms of action have not been evaluated in patients.

Methods A phase I, dose-escalation, biologic-end-point clinical trial of DNX-2401 was conducted in 37 patients with recurrent malignant glioma. Patients received a single intratumoral injection of DNX-2401 into biopsy-confirmed recurrent tumor to evaluate safety and response across eight dose levels (group A). To investigate the mechanism of action, a second group of patients (group B) underwent intratumoral injection through a permanently implanted catheter, followed 14 days later by en bloc resection to acquire post-treatment specimens.

Results In group A (n = 25), 20% of patients survived > 3 years from treatment, and three patients had a ≥ 95% reduction in the enhancing tumor (12%), with all three of these dramatic responses resulting in >3 years of progression-free survival from the time of treatment. Analyses of post-treatment surgical specimens (group B, n = 12) showed that DNX-2401 replicates and spreads within the tumor, documenting direct virus-induced oncolysis in patients. In addition to radiographic signs of inflammation, histopathologic examination of immune markers in post-treatment specimens showed tumor infiltration by CD8+ and T-bet+ cells, and transmembrane immunoglobulin mucin-3 downregulation after treatment. Analyses of patient-derived cell lines for damage-associated molecular patterns revealed induction of immunogenic cell death in tumor cells after DNX-2401 administration.

Conclusion Treatment with DNX-2401 resulted in dramatic responses with long-term survival in recurrent highgrade gliomas that are probably due to direct oncolytic effects of the virus followed by elicitation of an immune-mediated antiglioma response.

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Developing an Algorithm for Optimizing Care of Elderly Patients With Glioblastoma

Neurosurgery 82:64–75, 2018

Elderly patients with glioblastoma have an especially poor prognosis; optimizing their medical and surgical care remains of paramount importance.

OBJECTIVE: To investigate patient and treatment characteristics of elderly vs nonelderly patients and develop an algorithm to predict elderly patients’ survival.

METHODS: Retrospective analysis of 554 patients (mean age=60.8; 42.0% female) undergoing first glioblastoma resection or biopsy at our institution (2005-2011).

RESULTS: Of the 554 patients, 218 (39%) were elderly (≥65 yr). Compared with nonelderly, elderly patients were more likely to receive biopsy only (26% vs 16%), have ≥1 medical comorbidity (40% vs 20%), and develop postresection morbidity (eg, seizure, delirium; 25% vs 14%), and were less likely to receive temozolomide (TMZ) (78% vs 90%) and gross total resection (31% vs 45%). To predict benefit of resection in elderly patients (n = 161), we identified 5 factors known in the preoperative period that predicted survival in a multivariate analysis. We then assigned points to each (1 point: Charlson comorbidity score >0, subtotal resection, tumor >3 cm; 2 points: preoperative weakness, Charlson comorbidity score >1, tumor >5 cm, age >75 yr; 4 points: age >85 yr). Having 3 to 5 points (n = 78, 56%) was associated with decreased survival compared to 0 to 2 points (n = 41, 29%, 8.5 vs 16.9 mo; P = .001) and increased survival compared to 6 to 9 points (n = 20, 14%, 8.5 vs 4.5 mo; P < .001). Patients with 6 to 9 points did not survive significantly longer than elderly patients receiving biopsy only (n = 57, 4.5 vs 2.7 mo; P = .58).

CONCLUSION: Further optimization of the medical and surgical care of elderly glioblastoma patients may be achieved by providing more beneficial therapies while avoiding unnecessary resection in those not likely to receive benefit from this intervention.

 

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Awake Craniotomy vs Craniotomy Under General Anesthesia for Perirolandic Gliomas

Neurosurgery 81:481–489, 2017

A craniotomy with direct cortical/subcortical stimulation either awake or under general anesthesia (GA) present 2 approaches for removing eloquent region tumors. With a reported higher prevalence of intraoperative seizures occurring during awake resections of perirolandic lesions, oftentimes, surgery under GA is chosen for these lesions.

OBJECTIVE: To evaluate a single-surgeon’s experience with awake craniotomies (AC) vs surgery under GA for resecting perirolandic, eloquent, motor-region gliomas.

METHODS: Between 2005 and 2015, a retrospective analysis of 27 patients with perirolandic, eloquent, motor-area gliomas that underwent an AC were case-control matched with 31 patients who underwent surgery under GA for gliomas in the same location. All patients underwent direct brain stimulation with neuromonitoring and perioperative risk factors, extent of resection, complications, and discharge status were assessed.

RESULTS: The postoperative Karnofsky Performance Score (KPS) was significantly lower for theGApatients at 81.1 compared to theACpatients at 93.3 (P=.040). The extent of resection for GA patients was 79.6% while the AC patients had an 86.3% resection (P = .136). There were significantly more 100% total resections in the AC patients 25.9% compared to the GA group (6.5%; P=.041). Patients in theGAgroup had a longer mean length of hospitalization of 7.9 days compared to the AC group at 4.2 days (P = .049).

CONCLUSION: We show that AC can be performed with more frequent total resections, better postoperative KPS, shorter hospitalizations, as well as similar perioperative complication rates compared to surgery under GA for perirolandic, eloquent motor-region glioma.

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A method for safely resecting anterior butterfly gliomas

J Neurosurg 126:1795–1811, 2017

Gliomas invading the anterior corpus callosum are commonly deemed unresectable due to an unacceptable risk/benefit ratio, including the risk of abulia. In this study, the authors investigated the anatomy of the cingulum and its connectivity within the default mode network (DMN). A technique is described involving awake subcortical mapping with higher attention tasks to preserve the cingulum and reduce the incidence of postoperative abulia for patients with so-called butterfly gliomas.

METHODS The authors reviewed clinical data on all patients undergoing glioma surgery performed by the senior author during a 4-year period at the University of Oklahoma Health Sciences Center. Forty patients were identified who underwent surgery for butterfly gliomas. Each patient was designated as having undergone surgery either with or without the use of awake subcortical mapping and preservation of the cingulum. Data recorded on these patients included the incidence of abulia/akinetic mutism. In the context of the study findings, the authors conducted a detailed anatomical study of the cingulum and its role within the DMN using postmortem fiber tract dissections of 10 cerebral hemispheres and in vivo diffusion tractography of 10 healthy subjects.

RESULTS Forty patients with butterfly gliomas were treated, 25 (62%) with standard surgical methods and 15 (38%) with awake subcortical mapping and preservation of the cingulum. One patient (1/15, 7%) experienced postoperative abulia following surgery with the cingulum-sparing technique. Greater than 90% resection was achieved in 13/15 (87%) of these patients.

CONCLUSIONS This study presents evidence that anterior butterfly gliomas can be safely removed using a novel, attention-task based, awake brain surgery technique that focuses on preserving the anatomical connectivity of the cingulum and relevant aspects of the cingulate gyrus.

 

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